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Genes Dev. 2015 Feb 1;29(3):250-61. doi: 10.1101/gad.248963.114.

TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis.

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Graduate Program in Genetics, Stony Brook University, Stony Brook, New York 11794, USA;
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
3
Unit for Laboratory Animal Medicine, Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Abstract

The mechanisms by which TGF-β promotes lung adenocarcinoma (ADC) metastasis are largely unknown. Here, we report that in lung ADC cells, TGF-β potently induces expression of DOCK4, but not other DOCK family members, via the Smad pathway and that DOCK4 induction mediates TGF-β's prometastatic effects by enhancing tumor cell extravasation. TGF-β-induced DOCK4 stimulates lung ADC cell protrusion, motility, and invasion without affecting epithelial-to-mesenchymal transition. These processes, which are fundamental to tumor cell extravasation, are driven by DOCK4-mediated Rac1 activation, unveiling a novel link between TGF-β and Rac1. Thus, our findings uncover the atypical Rac1 activator DOCK4 as a key component of the TGF-β/Smad pathway that promotes lung ADC cell extravasation and metastasis.

KEYWORDS:

DOCK180 proteins; Rac1; TGF-β signaling; cell motility; lung adenocarcinoma metastasis; tumor cell extravasation

PMID:
25644601
PMCID:
PMC4318142
DOI:
10.1101/gad.248963.114
[Indexed for MEDLINE]
Free PMC Article

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